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[What is the use of even lower LDL cholesterol by combination therapy? A critical viewpoint].
Erdmann, E
Deutsche medizinische Wochenschrift (1946). 2015;(17):1314-5
Abstract
The IMPROVE-IT study has demonstrated a significant reduction of LDL-C when ezetimibe was given in addition to statins. Although the number of strokes and MI was reduced after 7 to 10 years of this treatment, mortality was unaffected, however. Additive ezetimibe treatment can be recommended only, if a better or longer life has been proved - which is not the case.
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Effect of combination therapy of ezetimibe and rosuvastatin on regression of coronary atherosclerosis in patients with coronary artery disease.
Masuda, J, Tanigawa, T, Yamada, T, Nishimura, Y, Sasou, T, Nakata, T, Sawai, T, Fujimoto, N, Dohi, K, Miyahara, M, et al
International heart journal. 2015;(3):278-85
Abstract
Ezetimibe has been reported to provide significant incremental reduction in low-density-lipoprotein cholesterol (LDL-C) when added to a statin; however, its effect on coronary atherosclerosis has not yet been evaluated in detail. The aim of this study was to investigate the add-on effect of ezetimibe to a statin on coronary atherosclerosis evaluated by intravascular ultrasound (IVUS).In this prospective randomized open-label study, a total of 51 patients with stable coronary artery disease (CAD) requiring percutaneous coronary intervention (PCI) were enrolled, and assigned to a combination group (n = 26, rosuvastatin 5 mg/day + ezetimibe 10 mg/day) or a monotherapy group (n = 25, rosuvastatin 5 mg/day). Volumetric IVUS analyses were performed at baseline and 6 months after the treatment for a non-PCI site. LDL-C level was significantly reduced in the combination group (-55.8%) versus that in the monotherapy group (-36.8%; P = 0.004). The percent change in plaque volume (PV), the primary endpoint, appeared to decrease more effectively in the combination group compared with the monotherapy group (-13.2% versus -3.1%, respectively, P = 0.050). Moreover, there was a significant group × time interaction in the effects of the two treatments on PV (P = 0.021), indicating the regressive effect of the combination therapy on PV was greater than that of monotherapy for subtly different values of baseline PV in the two treatment groups. Moreover, percent change in PV showed positive correlations with percent change of LDL-C (r = 0.384, P = 0.015).Intensive lipid-lowering therapy with ezetimibe added to usual-dose statin may provide significant incremental reduction in coronary plaques compared with usual-dose statin monotherapy.
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[Comparative Randomized Study of the Effects of Long-Term Therapy With Rosuvastatin and Combination of Atorvastatin and Ezetimibe on Carbohydrate Metabolism and Adipokines Levels in Patients With Coronary Artery Disease and Diabetes Mellitus].
Koshel'skaia, OA, Vinnitskaia, IV, Konko, TIu, Kravchenko, ES, Suslova, TE, Karpov, RS
Kardiologiia. 2015;(3):67-74
Abstract
OBJECTIVE This open randomized study compares the effects of 24-week-long treatment with rosuvastatin and with atorvastatin coadministered with ezetimibe on the parameters of carbohydrate metabolism and the plasma levels of adipokynes in patients with coronary artery disease and type 2 diabetes mellitus or impaired glucose tolerance (IGT). METHOD A total of 31 patients with coronary artery disease and type 2 diabetes mellitus or IGT were recruited in the study. Patients were randomized into two groups: group 1 included patients who received rosuvastatin therapy in an average dose of 12.5 mg/day (n = 16); group 2 included patients who received combination treatment with atorvastatin in an average dose of 13.3 mg/day and ezetimibe (10 mg) (n = 15). Plasma levels of lipids, apoB, apoA1, glucose, insulin, leptin, and adiponectin were evaluated; HOMA-IR index (an empty stomach insulin, mu/l x fasting glucose, mmol/l)/22.5) was calculated. RESULTS During the therapy, the LDL-C and apoB levels decreased by 51.7% and 42.3% in group 1 and by 51.8% and 44.9% in group 2, respectively. Reduction in the triglyceride levels was significantly more pronounced in group 2 than in group 1: 43.2% vs 17.4% (p < 0.02), whereas we did not observed significant changes of HDL-C and apoA1 in either group. The increases in basal glycemia, basal insulinemia, HbA1c levels (from 6.47% [6.10-7.02%] to 6.98% 16.23-8.18%]), and HOMA-IR (from 2.14 [1.68-3.51] to 4.30 [2.31-5.77]) were found only in group 2 (p < 0.05 for all). These changes were observed in 75% of patients of group 2 independently of the presence of diabetic state or IGT, but the changes were more pronounced in patients with disturbed carbohydrate metabolism. Changes of leptin levels during the therapy were diverse: 73% patients of group 1 demonstrated decrease in the leptin levels, whereas 67% of patients in group 2 experienced 57%-increase in the leptin concentrations. Degree of increased basal glycemia was associated with increase in the leptin levels (r = 0.37, p = 0.04) in the entire group of patients (n = 31). Furthermore, changes in leptin levels were negatively associated with decreased adiponectin levels (r = -0.57, p = 0.034). CONCLUSIONS In case of equivalent degree of the decrease in LDL-C levels, 24-week combination therapy with atorvastatin and ezetimibe, unlike rosuvastatin treatment, induced increases in basal glycemia, insulinemia, HbA1c, and HOMA-IR index irrespective of the presence of carbohydrate metabolism disturbances before treatment. Our data suggest that adiponectin and leptin are involved in the mechanisms of adverse metabolic effects of the combination of atorvastatin and ezetimibe.
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The effect of adding ezetimibe to rosuvastatin on renal function in patients undergoing elective vascular surgery.
Kouvelos, GN, Arnaoutoglou, EM, Milionis, HJ, Raikou, VD, Papa, N, Matsagkas, MI
Angiology. 2015;(2):128-35
Abstract
We compared the effects of lipid lowering with rosuvastatin (RSV) monotherapy versus intensified treatment by combining RSV with ezetimibe (EZT) on kidney function in patients undergoing vascular surgery. Patients were randomly assigned to either 10 mg/d RSV (n = 136) or RSV 10 mg/d plus EZT 10 mg/d (RSV/EZT, n = 126). At 12 months, a similar decrease in estimated glomerular filtration rate (eGFR) was noted. Patients who achieved a low-density lipoprotein cholesterol (LDL-C) of <100 mg/dL had less eGFR decrease than those patients having an LDL-C limit of more than 100 mg/dL. There were no significant changes in the urinary total protein to creatinine ratio in either group. Significant microalbuminuria was evident in both the groups. Patients undergoing vascular surgery show deterioration in their renal function during the first year, despite statin therapy. Intensified lipid-lowering therapy by adding EZT does not appear to have any renoprotective effect.
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Effects of lowering LDL cholesterol on progression of kidney disease.
Haynes, R, Lewis, D, Emberson, J, Reith, C, Agodoa, L, Cass, A, Craig, JC, de Zeeuw, D, Feldt-Rasmussen, B, Fellström, B, et al
Journal of the American Society of Nephrology : JASN. 2014;(8):1825-33
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Abstract
Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.
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High-dose simvastatin exhibits enhanced lipid-lowering effects relative to simvastatin/ezetimibe combination therapy.
Snowden, SG, Grapov, D, Settergren, M, D'Alexandri, FL, Haeggström, JZ, Fiehn, O, Hyötyläinen, T, Pedersen, TL, Newman, JW, Orešič, M, et al
Circulation. Cardiovascular genetics. 2014;(6):955-964
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Abstract
Statins are the frontline in cholesterol reduction therapies; however, their use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in low-density lipoprotein cholesterol. Thirty-nine patients were treated with either 80 mg simvastatin (n=20) or 10 mg simvastatin plus 10 mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable low-density lipoprotein cholesterol reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (eg, eicosanoids and endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. After statistical analysis and orthogonal projections to latent structures multivariate modeling, no changes were observed in lipid mediator levels, whereas global structural lipids were reduced in response to both monotherapy (R(2)Y=0.74; Q(2)=0.66; cross-validated ANOVA P=7.0×10(-8)) and combination therapy (R(2)Y=0.67; Q(2)=0.54; cross-validated ANOVA P=2.6×10(-5)). Orthogonal projections to latent structures modeling identified a subset of 12 lipids that classified the 2 treatment groups after 6 weeks (R(2)Y=0.65; Q(2)=0.61; cross-validated ANOVA P=5.4×10(-8)). Decreases in the lipid species phosphatidylcholine (15:0/18:2) and hexosyl-ceramide (d18:1/24:0) were the strongest discriminators of low-density lipoprotein cholesterol reductions for both treatment groups (q<0.00005), whereas phosphatidylethanolamine (36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease.
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Design and rationale of the GAUSS-2 study trial: a double-blind, ezetimibe-controlled phase 3 study of the efficacy and tolerability of evolocumab (AMG 145) in subjects with hypercholesterolemia who are intolerant of statin therapy.
Cho, L, Rocco, M, Colquhoun, D, Sullivan, D, Rosenson, RS, Dent, R, Xue, A, Scott, R, Wasserman, SM, Stroes, E
Clinical cardiology. 2014;(3):131-9
Abstract
Statins effectively lower low-density lipoprotein cholesterol (LDL-C), reducing cardiovascular morbidity and mortality. Most patients tolerate statins well, but approximately 10% to 20% experience side effects (primarily muscle-related) contributing to diminished compliance or discontinuation of statin therapy and subsequent increase in cardiovascular risk. Statin-intolerant patients require more effective therapies for lowering LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a compelling target for LDL-C-lowering therapy. Evolocumab (AMG 145) is a fully human monoclonal antibody that binds PCSK9, inhibiting its interaction with the LDL receptor to preserve LDL-receptor recycling and reduce LDL-C. Phase 2 studies have demonstrated the safety, tolerability, and preliminary efficacy of subcutaneous evolocumab in diverse populations, including statin-intolerant patients. This article describes the rationale and design of the Goal Achievement After Utilizing an anti-PCSK9 Antibody in Statin-Intolerant Subjects 2 (GAUSS-2) trial, a randomized, double-blind, ezetimibe-controlled, multicenter phase 3 study to evaluate the effects of 12 weeks of evolocumab 140 mg every 2 weeks or 420 mg every month in statin-intolerant patients with hypercholesterolemia. Eligible subjects were unable to tolerate effective doses of ≥2 statins because of myalgia, myopathy, myositis, or rhabdomyolysis that resolved with statin discontinuation. The primary objective of the study is to assess the effects of evolocumab on percentage change from baseline in LDL-C. Secondary objectives include evaluation of safety and tolerability, comparison of the effects of evolocumab vs ezetimibe on absolute change from baseline in LDL-C, and percentage changes from baseline in other lipids. Recruitment of approximately 300 subjects was completed in August 2013.
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[IMPROVE-IT Study proves effectiveness of ezetimib. The Higgs particle of lipidologists].
Einecke, D
MMW Fortschritte der Medizin. 2014;(21-22):24-6
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Effects of ezetimibe on endothelial progenitor cells and microparticles in high-risk patients.
Lins, LC, França, CN, Fonseca, FA, Barbosa, SP, Matos, LN, Aguirre, AC, Bianco, HT, do Amaral, JB, Izar, MC
Cell biochemistry and biophysics. 2014;(1):687-96
Abstract
Imbalance on endothelial turnover can predict cardiovascular outcomes. We aimed at evaluating the effects of lipid-modifying therapies on circulating endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), and platelet microparticles (PMPs) in high cardiovascular risk subjects with elevated C-reactive protein (CRP). Sixty-three individuals with coronary heart disease (CHD) or CHD risk equivalent on stable statin therapy, with LDL-cholesterol <100 mg/dL and CRP ≥ 2.0 mg/L were selected. After a 4-week run-in period with atorvastatin 10 mg, those with persistent CRP ≥ 2.0 mg/L were randomized to another 4-week treatment period with atorvastatin 40 mg, ezetimibe 10 mg or atorvastatin 40 mg/ezetimibe 10 mg. EPC (CD34(+)/CD133(+)/KDR(+)), EMP (CD51(+)), and PMP (CD42(+)/CD31(+)) were quantified by flow cytometry. Atorvastatin 40 mg and atorvastatin 40 mg/ezetimibe 10 mg reduced LDL-cholesterol (P < 0.001, paired T test, vs. baseline). Combined therapy, but not ezetimibe reduced CRP. CD34(+)/KDR(+) EPC were reduced after ezetimibe alone (P = 0.011 vs. baseline, Wilcoxon test) or combined with atorvastatin (P = 0.016 vs. baseline, Wilcoxon test). In addition, ezetimibe increased CD51(+) EMP (P = 0.017 vs. baseline, Wilcoxon test). No correlations between these markers and LDL-cholesterol or CRP were observed. These results contribute to understand the link between inflammation and vascular homeostasis and highlight the broader benefit of statins decreasing inflammation and preventing microparticles release, an effect not observed with ezetimibe alone.
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The effect of lowering LDL cholesterol on vascular access patency: post hoc analysis of the Study of Heart and Renal Protection.
Herrington, W, Emberson, J, Staplin, N, Blackwell, L, Fellström, B, Walker, R, Levin, A, Hooi, LS, Massy, ZA, Tesar, V, et al
Clinical journal of the American Society of Nephrology : CJASN. 2014;(5):914-9
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Abstract
BACKGROUND AND OBJECTIVES Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with CKD, including dialysis patients, but the effect of lowering LDL-C on vascular access patency is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to 20 mg simvastatin plus 10 mg ezetimibe daily versus matching placebo. This study aimed to explore the effects of treatment on vascular access occlusive events, defined as any access revision procedure, access thrombosis, removal of an old dialysis access, or formation of new permanent dialysis access. RESULTS Among 2353 SHARP participants who had functioning vascular access at randomization, allocation to simvastatin plus ezetimibe resulted in a 13% proportional reduction in vascular access occlusive events (355 [29.7%] for simvastatin/ezetimibe versus 388 [33.5%] for placebo; risk ratio [RR], 0.87; 95% confidence interval [95% CI], 0.75 to 1.00; P=0.05). There was no evidence that the effects of treatment differed for any of the separate components of this outcome. To test the hypothesis raised by SHARP, comparable analyses were performed using the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial cohort. AURORA did not provide independent confirmation (vascular access occlusive events: 352 [28.9%] for rosuvastatin versus 337 [27.6%] for placebo; RR, 1.06, 95% CI, 0.91 to 1.23; P=0.44). After combining the two trials, the overall effect of reducing LDL-C with a statin-based regimen on vascular access occlusive events was not statistically significant (707 [29.3%] with any LDL-C-lowering therapy versus 725 [30.5%] with placebo; RR, 0.95, 95% CI, 0.85 to 1.05; P=0.29). CONCLUSIONS Exploratory analyses from SHARP suggest that lowering LDL-C with statin-based therapy may improve vascular access patency, but there was no evidence of benefit in AURORA. Taken together, the available evidence suggests that any benefits of lowering LDL-C on vascular access patency are likely to be modest.